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RETRACTED ARTICLE: Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model

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This article was retracted on 26 December 2023

This article has been updated

Abstract

Purpose

Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine.

Methods

We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints’ expression.

Results

Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen.

Conclusion

These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.

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Data Availability

All relevant information is presented within the article. Additional data that support the findings of this study are available from the corresponding author upon reasonable request.

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ACKNOWLEDGMENTS AND DISCLOSURES

We are very grateful for the financial support of Urmia University of Medical Sciences (grant number:10954) and Tabriz University of Medical Sciences (grant numbers: 66472 and 66443) for this study. We also thank the National Institute for Medical Research Development, NIMAD, for supporting this study (grant number: 4000524). We would also like thank to Koosha Koorehpaz and Mehran Mozaffari for their excellent contribution in this study. There is no conflict of interest.

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Author notes

  1. Asal Barshidi and Vahid Karpisheh are equally contributed to this study.

Authors and Affiliations

  1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Asal Barshidi, Fariba Karoon Kiani, Sanam Nami, Pooya Jalali & Farhad Jadidi-Niaragh

  2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Vahid Karpisheh

  3. Department of Biotechnology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran

    Fatemeh Karimian Noukabadi

  4. Department of Cell and Molecular Biology, School of Advanced Sciences, Islamic Azad University, Tehran Medical Branch, Tehran, , Iran

    Mohammad Mohammadi

  5. Department of Microbiology, Faculty of Basic Sciences, Hamedan Branch, Islamic Azad University, Hamedan, Iran

    Negin Afsharimanesh

  6. Nanoparticle Process Technology, Faculty of Engineering, University of Duisburg-Essen, Duisburg, Germany

    Farbod Ebrahimi

  7. Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Seyed Hossein Kiaie

  8. Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Seyed Hossein Kiaie

  9. Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran

    Jamshid Gholizadeh Navashenaq

  10. Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden

    Mohammad Hojjat-Farsangi

  11. The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran

    Mohammad Hojjat-Farsangi

  12. Experimental and Applied Pharmaceutical Sciences Research Center,, Urmia University of Medical Sciences, Urmia, Iran

    Naime Majidi Zolbanin

  13. Department of Pharmacology and Toxicology, School of Pharmacy, , Urmia University of Medical Sciences, Urmia, Iran

    Naime Majidi Zolbanin

  14. Department of Anesthesiology, School of Medicine, Imam Reza Medical Research & Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran

    Ata Mahmoodpoor

  15. Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Hadi Hassannia

  16. Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran

    Reza Jafari

  17. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Farhad Jadidi-Niaragh

  18. Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran

    Farhad Jadidi-Niaragh

Authors
  1. Asal Barshidi
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  2. Vahid Karpisheh
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  3. Fatemeh Karimian Noukabadi
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Contributions

Conceptualization: Asal Barshidi, Vahid Karpisheh, Mohammad Hojjat-Farsangi, Naime Majidi Zolbanin. Data curation: Asal Barshidi, Hadi Hassannia, Sanam Nami, Fariba Karoon Kiani, Negin Afsharimanesh, Jamshid Gholizadeh Navashenaq. Formal analysis: Asal Barshidi, Vahid Karpisheh, Fariba Karoon Kiani, Negin Afsharimanesh, Jamshid Gholizadeh Navashenaq, Ata Mahmoodpoor. Funding acquisition: Ata Mahmoodpoor, Reza Jafari, Farhad Jadidi-Niaragh, Fatemeh Karimian Noukabadi. Methodology: Asal Barshidi, Vahid Karpisheh, Hadi Hassannia, Jamshid Gholizadeh Navashenaq, Sanam Nami, Pooya Jalali1 Project administration: Farbod Ebrahimi, Seyed Hossein Kiaie, Reza Jafari, Farhad Jadidi-Niaragh.

Writing-review and editing: Reza Jafari, Farhad Jadidi-Niaragh.

Corresponding authors

Correspondence to Reza Jafari or Farhad Jadidi-Niaragh.

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Barshidi, A., Karpisheh, V., Noukabadi, F.K. et al. RETRACTED ARTICLE: Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model. Pharm Res 39, 1851–1866 (2022). https://doi.org/10.1007/s11095-022-03297-9

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